BioWorld International Correspondent
LONDON - French researchers are confident that a new therapy to treat patients with schizophrenia will be available within a decade, following their discovery of a previously unknown gene that is mutated in people with the disease. The gene, called G72, is absent from the annotated map of the human genome, thus begging the question of how many other genes may remain lurking in the "genomic deserts" of "junk DNA."
Daniel Cohen, chief scientific officer of Genset SA, of Evry, told BioWorld International that mutations also are present in G72 in patients with bipolar disease, according to his team's preliminary findings.
He predicted that it would be easy to develop a molecule that would inhibit the enzyme that appears to be overactive in schizophrenia. Scientists at Serono International SA, of Geneva, which acquired Genset last month, are intending to explore ways of designing such molecules, he said.
Cohen described his group's search for a gene involved in schizophrenia, which began in 1997, as a "nightmare. We had to solve so many problems along the way, including developing a new technique for identifying genes in the human genome sequence . . . but in the end we were lucky," he said.
Cohen and his collaborators report their findings in a paper published online in the Oct. 15, 2002, issue of the Proceedings of the National Academy of Sciences titled "Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia."
At the start of their search, classical linkage analysis had shown that a region of chromosome 13, 5 megabases long, contained several genetic markers that were significantly linked with the inheritance of both schizophrenia and bipolar disease. So the team sequenced the entire region, developing a high-density map of single nucleotide polymorphisms (SNPs).
The researchers then looked at two large study populations, each containing people with schizophrenia and controls, one from Quebec and the other from Russia. Having first checked that each of the populations was genetically homogeneous, they looked to see which SNPs the cases and controls had, within the 5-megabase stretch for which the detailed SNP map was available. In both populations, they found a significant peak of association between particular SNPs in cases compared with controls, within a very small region, of around 65 kilobases.
"But it was a big surprise to us," Cohen said, "that, according to the map of the human genome, no genes had been annotated in this region. It was in what is known as a genomic desert."
One of the main methods for finding genes within the human genome sequence has been to find genes that resemble those already known from other living organisms. "This method relies on the fact that most genes are conserved between species," Cohen said. "So we hypothesized that this gene had not been conserved."
To identify non-conserved genes, they developed a new technique, which they called "experimental annotation." They made one probe per kilobase of the non-annotated sequence, and used these probes to scan, using the polymerase chain reaction, a library of brain messenger RNA. That allowed them to discover three genes, one at the exact position of the 65-kilobase region they had been studying.
Further investigations showed that the gene, which they called G72, was expressed only in brain and spinal cord. It was absent from mice, but present in an altered form in some monkeys and in gorillas. Experiments also showed that the G72 protein is a strong activator of an enzyme called D-amino acid oxidase (DAAO), which in turn degrades an amino acid called D-serine.
"Here, the story is starting to make sense," Cohen said. "D-serine is known to activate the brain receptor called NMDA - and it was postulated some time ago that schizophrenia could be due to hypoactivity of the NMDA receptor. So the hypothesis would be that if some people were to overproduce G72 for genetic reasons, then DAAO activity would increase, there would be less D-serine and, therefore, less NMDA activity."
The team went on to look for SNPs in the gene for DAAO and were again able to show a correlation between inheritance of certain SNPS and schizophrenia. Finally, they showed that mutations in both genes were additive, a phenomenon known as genetic interaction.
"We found that the risk of having schizophrenia for people carrying certain SNPs in G72 and in DAAO was about five times greater than those who did not have these mutations. For those with mutations in either G72 or DAAO, it was only about 1.5 times greater," Cohen said. "This suggests strongly that both G72 and DAAO belong to the same pathological pathway triggering schizophrenia. The way forward for drug development is to develop an inhibitor of DAAO, which would result in an increase in the D-serine level, and thus in NMDA activity."
In bipolar disease, Cohen and his collaborators have preliminary results suggesting that there is an association with mutations in G72. Their study to find out if the same holds true for DAAO mutations is continuing.